Dopaminergic benzazepines

ABSTRACT

A new series of compounds having renal vasodilating activity is described. The compounds are 3-cycloalkylmethyl-7,8-dihydroxy-6-halo-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines.

This invention comprises a group of new chemical compounds which are3-cycloalkylmethyl-7,8-dihydroxy-6-halo-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines.These compounds increase blood flow in the kidney by decreasing vascularresistance mainly by means of a dopaminergic effect on peripheraldopamine receptors. As such they are useful for treating hypertension.

DESCRIPTION OF THE PRIOR ART

A number of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines have beendescribed which have renal dopaminergic activity such as U.S. Pat. Nos.4,160,765; 4,197,297 and 4,251,525. These prior art compounds do nothave the combination of structural features present in the compounds ofthis invention especially the 3-cycloalkylmethyl substituent. A numberof other patents such as U.S. Pat. No. 3,609,138 or U.K. Pat. No.1,268,243 disclose cycloalkylalkyl substituents at the 3-position of2,3,4,5-tetrahydro-1H-3-benzazepines but for compounds having activityin a different therapeutic indication and with broad genericdisclosures.

DESCRIPTION OF THE INVENTION

The compounds of this invention have structures characterized by a2,3,4,5-tetrahydro-1H-3-benzazepine nucleus substituted by acycloalkylmethyl group at position 3, a halo at position 6, two hydroxygroups at positions 7 and 8 and a hydroxyphenyl moiety at position 4.The compounds therefore may be represented by the following structuralformula: ##STR1## in which R is halo, that is, chloro, bromo, fluoro oriodo and n is an integer of from 1-4. Of particular interest are thosecompounds of Structure I in which n is 1.

The three phenolic hydroxy groups may also be derivatized by formingtri-lower alkanoyl esters. Each of the lower alkanoyl groups has from2-7 carbon atoms. For convenience in preparation, the same alkanoylgroup is used at each position.

The pharmaceutically acceptable acid addition salts having the utilityof the free bases of Formula I, prepared by methods well known to theart, are formed with both inorganic and organic acids, for example:fumaric, ascorbic, succinic, methane sulfonic, ethanedisulfonic, acetic,tartaric, salicylic, citric, gluconic, itaconic, glycolic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic,phosphoric and nitric acids. The hydrohalic and especially methanesulfonic acid salts are of particular utility.

The compounds of this invention are prepared by a synthetic sequence-thefirst step of which involves the N-acylation of a known6-halo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(U.S. Pat. No. 4,160,765) with a cycloalkyl carboxylic acid or its acidhalide to give the N-cycloalkylcarbonyl compound which is then reducedwith metallic reducing agent such as lithium aluminum hydride, sodiumborohydride, sodium cyanoborohydride, lithium triethylborohydride,sodium trimethoxyborohydrate and other metallic hydride reducing agents.

The reducing step is conveniently carried out in a solvent in which thereactants are soluble such as tetrahydrofuran at temperatures from 40°up to reflux temperature. The desired products are isolated by methodsknown to the art.

Most conveniently the acylation-reduction steps can be combined using acycloalkylcarboxylic acid and the secondary base as starting materialwith sodium borohydride in tetrahydrofuran at 50°-60° until the reactionis complete.

Of particular interest is the final step of the reaction sequence inwhich the3-cycloalkylmethyl-6-halo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineor one of its acid addition salts is reacted with an ether cleavingagent. Thr reaction readily proceeds with boron tribromide or borontrichloride in a halogenated organic solvent such as methylene chloride,carbon tetrachloride or chloroform. Alternative ether cleaving agentsare pyridine hydrochloride, 48% aqueous hydrogen bromide, aluminumchloride or bromide in a suitable organic solvent such as benzene orcarbon disulfide, 57% hydrogen iodide, hydrogen fluoride-antimonypentafluoride or trifluoromethylsulfonic acid in thioanisole. Theproduct is isolated by methods known to the art.

Details of this reaction sequence are described in the exemplarymaterial presented below. Other variations of the reaction sequence orindeed other synthetic paths to the final products will be apparent tothose skilled in the art. Other O-protecting groups are useful such asbenzyl, other lower alkyl groups for example ethyl, propyl, or for6,7-hydroxy groups taken together, methylene or ethylene.

The renal dopaminergic activity of the compounds of this invention wasdemonstrated by monitoring mean arterial blood pressure (MAP), meanrenal blood flow (RBF), renal vascular resistance (RVR) and heart rate(HR) in a normal anesthetized dog in a standard pharmacologicalprocedure. The selected compound is administered by intravenous infusionand is expressed as μg/kg/min. Each dose is infused for five minutes. Aclinically useful compound, dopamine, was run as a positive control.

    ______________________________________                                        Compound A: 3-Cyclopropylmethyl-6-chloro-7,8-dihydroxy-1-                     (p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-                                    benzazepine hydrobromide:                                                      Dose          % Change in 2 Dogs                                             (μg/kg/min) MAP      RBF      RVR   HR                                     ______________________________________                                        Dopamine                                                                               3          -6.9    +28.6  -27.2 +10.7                                A        3         -3.1      -2.0   -0.5 +0.1                                         30         -0.7     +14.1  -12.6 0                                            300        -11.5    +18.2  -25.8 -3.2                                 ______________________________________                                    

The desired vasodilator activity accompanied by increase in renal bloodflow was observed at doses of 30 and 300 μg/kg/min.

The pharmacodynamic methods of this invention comprise administration ofan active nontoxic quantity of a compound of Formula I, one of itspharmaceutically acceptable acid addition salts or one of its O-loweralkanoyl esters internally, preferably either orally or parenterally, toa human or animal patient in need or renal vasodilation. The primarydesired effect on the kidney is to decrease vascular resistance andincrease blood flow. The effect is similar to the renal effects ofdopamine and like clinical effects may be thereby realized such as intreating hypertension or other abnormal cardiovascular conditions. Theroute of administration may be any that effectively transports theactive ingredient to the renal receptors but oral, rectal, intravenousor subcutaneous routes of administration are conveniently used. Thecompound of Formula I is administered in a nontoxic quantity sufficientto induce renal vasodilatation. Most conveniently the active ingredientis combined with a pharmaceutical carrier and administered to thepatient from 1-5 times daily as necessary to effect the desiredpharmacodynamic result. The daily dosage is based on total quantities ofthe base of from about 200 mg to about 1 g per day, administeredpreferably as 100-500 mg of base per dosage unit which is administeredfrom 1-5 times daily orally. The parenteral dosage regimen would belower than the oral regimen. The daily dosage regimen is selected withthe conditions known to be factors in the art, for example, the age andweight of the subject, the severity of the clinical disorder, the routeof administration and the relative potency of the active ingredientcompared to the activity of dopamine in the test systems describedhereafter. When the method of this invention is carried out renalvasodilatation similar to that induced by dopamine is realized.

The pharmaceutical compositions of this invention having renal dilatingactivity which are of use for treating hypotensive patients are preparedin conventional dosage unit forms by incorporating a compound of FormulaI, or a pharmaceutically acceptable acid addition salt or esterderivative thereof, with a nontoxic pharmaceutical carrier according toaccepted procedures in a nontoxic amount sufficient to produce thedesired pharmacodynamic activity in a subject, animal or human.Preferably, the compositions will contain the active ingredient in anactive but nontoxic amount selected from about 100 mg to about 500 mgpreferably about 125-350 mg of active ingredient calculated as the baseper dosage unit.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid,and the like. Exemplary of liquid carriers are isotonic saline forparenteral use or syrup, peanut oil, olive oil, water and the like forsoft gelatin capsules. Similarly, the carrier or diluent may include anytime delay material well known to the art, such as glyceryl monostearateor glyceryl distearate alone or with a wax. Such sustained releaseproducts as well as derivatives which may be gradually metabolized tothe active parent can be employed to prolong the biological activity ofthe compounds of this invention.

A wide variety of pharmaceutical forms can be employed ranging fromrectal suppositories to sterile solutions for parenteral or injectableuse. Thus, if a solid carrier for oral administration is used thepreparation can be tableted, placed in a hard gelatin capsule in powder,regular or sustained release pellet or tablet form, or in the form of atroche or lozenge. The amount of solid carrier will vary widely butpreferably will be from about 25 mg to about 1 g. If a liquid carrier isused, the preparation will be in the form of a syrup, emulsion, softgelatin capsule, sterile injectable liquid such as an ampul or anaqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingredients as appropriate to give the desired end product.

The following examples are designed to teach the practice of theinvention but not to limit its scope. All temperatures are Centigrade.

EXAMPLE 1

A mixture of 2.0 g (0.0058 m) of6-chloro-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,15 g (0.11 m) of cyclopropanecarboxylic acid and 25 ml oftetrahydrofuran was stirred under nitrogen at 50°-55° while 1.0 g (0.027m) of sodium borohydride was added over a 30 minute period. Reaction wascontinued for 4 hours under a nitrogen atmosphere. The reaction mixturewas cooled and diluted with 50 ml of cold water. The aqueous mixture wasmade strongly basic with sodium hydroxide then extracted with methylenechloride. The extract was washed twice with brine, water and then brineagain. Evaporation of the dried organic extract gave 2.4 g of yellowoil. Thin layer chromatography showed a mixture present.

The yellow oil in chloroform was passed over a silica gel column andeluted using 2% methanol-chloroform to give 2.1 g of the desired base.The base was converted with hydrogen chloride-methanol to 1.58 g (69%)of the hydrochloride salt of3-cyclopropylmethyl-6-chloro-7,8-dimethoxy-1-(p-methoxy-phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,m.p. 146°-149°.

The trimethoxyhydrochloride (0.98 g, 0.0022 m) in 25 ml of methylenechloride was cooled to -15° then reacted with a mixture of 1.2 ml (0.013m) of boron tribromide and 10 ml of methylene chloride. After stirringat -15° for one half hour and at room temperature for 2 hours, themixture was cooled and quenched several times with methanol, the lasttime with a few drops of 48% hydrogen bromide. Evaporation gave a foamwhich was crystallized from ethyl acetate-methanol to give 0.87 g (90%)of white solid3-cyclopropylmethyl-6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 215°-218°.

Anal. Calcd. for C₂₀ H₂₂ ClNO₃.HBr: C, 54.50; H, 5.26; N, 3.18. Found:C, 54.48; H, 5.10; N, 3.04.

This compound (150 mg) is mixed with 150 mg of lactose and 2 mg ofmagnesium stearate then filled into hard gelatin capsule which isadministered orally to a hypertensive patient 5 times daily.

Another portion of 500 mg of the hydrobromide salt is shaken with amixture of ether-5% sodium carbonate solution. The ether layer isdivided into three aliquots. Reaction with methane sulfonic acid inethanol, sulfuric acid in ether or evaporation gives the methanesulfonic acid salt, sulfate or base forms respectively.

EXAMPLE 2

A mixture of 2.0 g of6-fluoro-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, 2.8 g of triethylamine and 25 ml of dimethylformamide isstirred at room temperature then cooled to 0° while 2 g of cyclobutanecarboxylic acid chloride is added dropwise. After stirring at roomtemperature for 2 hours, the mixture is poured into water and thedesired 3-cyclobutylcarbonyl intermediate isolated by ethyl acetateextraction.

This material (1 g) in tetrahydrofuran is added dropwise to a suspensionof 2.5 g of lithium aluminum hydride in tetrahydrofuran. After stirringthe reaction mixture at room temperature overnight, ethyl acetate isadded followed by an aqueous solution of ammonium tartrate. The organiclayer is separated, evaporated and the residue purified by chloroformextraction and formation of the hydrochloride salt,3-cyclobutylmethyl-6-fluoro-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride.

This material (0.8 g) in 20 ml of methylene chloride is reacted withboron tribromide (2.0 ml) in 20 ml of methylene chloride at -15°. Aftermethanol quenching, evaporation gives3-cyclobutylmethyl-6-fluoro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineas the hydrobromide.

EXAMPLE 3

The procedure of Example 2 is repeated with6-iodo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand cyclopentanecarboxylic acid chloride as starting materials to givethe N-cyclopentylcarbonyl compound then3-cyclopentylmethyl-6-iodo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, and finally3-cyclopentylmethyl-6-iodo-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

EXAMPLE 4

6-Bromo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide (3 g) is reacted with cyclohexylcarboxylic acid in thepresence of sodium borohydride as in Example 1 to give6-bromo-3-cyclohexylmethyl-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinebase and, after treatment with boron tribromide,6-bromo-3-cyclohexylmethyl-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

EXAMPLE 5

A mixture of 1 g of3-cyclopropylmethyl-6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, 1.3 ml of acetyl bromide and 200 ml of trifluoroaceticacid is heated at reflux for 2 hours. After evaporation to dryness, theresidue is purified, if necessary, by recrystallization to give3-cyclopropylmethyl-6-chloro-7,8-diacetoxy-1-(p-acetoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide. Similarly tri-isobutyryloxy, -propionyloxy,-isovaleryloxy, -n-butyryloxy and -n-heptanoyloxy ester derivatives areprepared.

What is claimed is:
 1. A compound of the structure ##STR2## in which Ris halo and n is 1, one of its tri-O-lower alkanoyl esters or one of itspharmaceutically acceptable acid addition salts.
 2. The compound ofclaim 1 being6-chloro-3-cyclopropylmethyl-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine.3. The compound of claim 1 being6-chloro-3-cyclocyclopropylmethyl-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinein the form of a pharmaceutically acceptable acid addition salt.
 4. Thecompound of claim 1 being6-chloro-3-cyclopropylmethyl-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinemethane sulfonic acid salt.